The present invention relates to sterilization of target objects by inactivation of microorganisms located thereon and/or therein. More particularly, the present invention relates to parametric control of the pulsed light sterilization of target objects. Still more particularly, described herein are methods and apparatus for parametric control of the sterilization of target objects by deactivation of microorganisms on packages, on or within unpackaged objects and/or on or within the contents of packages, using high-intensity, short-duration pulses of incoherent, polychromatic light in a broad spectrum. Even more particularly, the present invention relates to monitoring and controlling key pulsed light parameters in the deactivation of microorganisms on and/or within target objects using high-intensity, short-duration pulses of incoherent, polychromatic light in a broad spectrum to verify sterilization has been achieved. In a particular embodiment, parametric control of the pulsed light sterilization of the contents of appropriately selected transmissive packaging is described.
Various methods of sterilization are known to those of skill in the art, including for example, heat sterilization, e.g., autoclaving, irradiation sterilization, e.g., using gamma radiation, and chemical sterilization. A more recently developed, and hence less well known, method of deactivating microorganisms on and/or within a target object involves the use of high-intensity, short-duration pulses of incoherent, polychromatic light in a broad spectrum. A significant advantage to this newly developed sterilization and deactivation method is the speed with which it can be accomplished. Most target objects are sterilized or decontaminated within less than a few minutes as only a few flashes, having durations of a few seconds to less than a minute, are required.
Commonly, target objects that are to be sterilized must be further manipulated, after sterilization, to validate the sterilization procedure. For example, if a batch of medical instruments is sterilized using a heat method of sterilization (autoclaving, for example), the so treated instruments may not be used until a random few of them have been tested to confirm that the sterilization method was effective. Typically, the batch of treated products is set aside for a predetermined waiting period following which a few are selected to be tested for the presence of contaminating microorganisms. Assuming the random sampling of batch-treated target objects are demonstrated to be sterile, then the entire batch is released for use. Thus, it can be seen that heretofore known processes of sterilization of target objects are inefficient in that they require further manipulation and testing of the target objects to validate the success of the sterilization, thereby increasing the time necessary to achieve sterilization and increasing the overall costs of such.
Another issue surrounding the need for validation of sterilization processes, is the issue of insuring effective sterilization of target objects contained within packaging. For example, in the case of autoclaving (i.e., heat sterilization), the target object is frequently placed into a package prior to sterilization. Thus, validation is particularly important in order to accommodate the added variable of the packaging material and its affect on the sterilization process. In the case of broad spectrum pulsed light sterilization methods, packaging materials are of particular concern as they must be sufficiently transmissive to the sterilizing light to permit full contact of the light with the target object contained therein.
Polyvinyl Chloride (PVC) is a standard, widely used plastic packaging material used to manufacture flexible containers (bags and pouches) for the administration of small volume parenterals (SVPs), often referred to as mini-bags; large volume parenterals (LVPs); and various enteral nutritional and liquid preparations. These containers are often utilized for patient hydration and/or to supply pharmaceutical preparations, medicines, vitamins, nutritionals, and the like. Heretofore, PVC has proven to be advantageous because of its resistance to heat, which allows the containers to be terminally sterilized using high temperature treatment, i.e., sterilized after filling to deactivate microorganisms inside the containers, including microorganisms suspended in liquid content of the container, using high temperature treatment (e.g., autoclaving).
In many cases, an overwrap is also used to help the flexible containers to survive autoclaving (i.e., high temperature treatment), and also to increase the shelf life of parenteral fluids contained therein by providing improved moisture vapor barrier (MVB) properties, as compared to the MVB properties of PVC alone. In many cases, and particularly for SVP packages (or bags), multiple SVP packages are placed into one overwrap package. Disadvantageously, once the one overwrap package has been opened, the shelf life of the individual SVP packages contained therein is limited to approximately 30 days, because of the poor MVB properties of PVC. Thus, if a practitioner opens an overwrap containing SVPS, but does not use all of the SVPs in a timely manner, the SVP packages must be discarded approximately 30 days after the overwrap is opened. The overwrap also represents a significant added packaging cost and contributes to environmental waste.
Using materials other than PVC, such as olefins (e.g., polyethylene or polypropylene); nylon, or a composite material, having either a laminated or co-extruded structure (including both monolayer and multilayer structures), and the like, for SVP, LVP and/or enteral packages offers a number of significant advantages. One advantage is to reduce or eliminate the use of PVC because of environmental concerns. Another advantage of materials such as polyethylene is that they have much better MVB properties than PVC. For example, in some instances, it may be possible to achieve a longer shelf life (for example, 24 months versus the 15 to 18 months achievable with PVC and overwrap) without the inconvenience and added cost of the overwrap.
Another advantage to replacing PVC with a material such as polyethylene is that products such as pure deionized water (U.S.P. for injection) cannot be effectively packaged in PVC because by-products from the PVC packaging material leach into the pure deionized water, contaminating it, whereas materials such as polyethylene can be formulated so as not to contain by-products that leach into the pure deionized water.
Empty parenteral and enteral containers are also widely used, with liquid contents typically being manually added after delivery of the containers by a pharmacist or dietitian. These empty containers, heretofore typically produced in PVC, are often terminally sterilized using autoclaving. However, these empty containers also suffer from the problems described above. Thus, advantages exist to using olefin, nylon and composite materials for containers, such as parenteral and enteral containers.
Unfortunately, heretofore known methods of terminal sterilization, such as autoclaving, are unsuitable for use with polyethylene containers or thin polypropylene containers, because such containers are unable to withstand the temperatures (e.g., between 100 and 200xc2x0 C.) or pressures of autoclaving. (Polypropylene containers are able to withstand some amount of commercially useful autoclaving, however, are required to be thicker and more expensive to withstand autoclaving than would need be in the absence of this high heat and pressure treatment.) Thus, there exists a need for an approach to deactivating microorganisms through a container that does not require the use of heat that may damage the container or its contents.
Other processes, such as the process suggested by Beigler, et al. in the U.S. Pat. No. 4,282,863, entitled METHODS OF PREPARING AND USING INTRAVENOUS NUTRIENT COMPOSITIONS, issued Aug. 11, 1981, employ gamma radiation to achieve terminal sterilization. Unfortunately, the use of gamma radiation creates other problems. For example, gamma radiation is prone to altering the polymeric structure of the olefin container (i.e,, gamma radiation degrades the product container integrity), which can result in weakened container integrity, leakage, increased gas permeability and other such problems. Also gamma radiation can attack the package and/or its contents to produce other adverse changes, such as darkening, off-colors or color changes, etc. in the package or its contents. Furthermore, gamma radiation inherently causes the generation of highly reactive species, such as hydroxyl radicals produced during the gamma radiation of water, that may detrimentally alter the chemical structure of the product being treated. Thus, there exists a need for an improved sterilization process usable with polyolefins and the like that does not employ gamma radiation, or other such reactive processes, to achieve sterilization.
As mentioned previously, other problems with heat treatment, i.e., autoclaving, and heretofore employed gamma radiation treatment techniques include the xe2x80x9cbatchxe2x80x9d nature of such processes. Specifically, with heat or gamma radiation treatment, products and/or product containers are treated in groups or batches, which problematically requires additional handling of the product not required if an on-line continuous process is used. In addition, careful inventorying and product handling are required in order to assure that each batch is segregated, and separately treated and tested.
In addition, with heretofore employed terminal sterilization techniques, it is nearly impossible to monitor all of the parameters necessary to assure adequate deactivation of microorganisms in all of the product packages in a given batch (i.e., parametric control is nearly impossible). (For example, it is difficult to monitor the temperature within the autoclave at enough points than one can assure that every part of every target object in the batch received enough heat and saturated steam pressure to achieve adequate deactivation of microorganisms.) Because such parametric control is not generally possible with heretofore employed terminal sterilization techniques, the target objects must be observed for a period of time, e.g., for fourteen days, following terminal sterilization to determine whether any contaminants are present in selected (or all) objects from each batch. This, unfortunately, further complicates product and product container treatment and delays usage of the packages and/or products having been treated. An approach that can be performed in a continuous manner, e.g., as a part of a packaging process, can eliminate the need for xe2x80x9cbatchxe2x80x9d handling and xe2x80x9cbatchxe2x80x9d testing. Further, a sterilization approach that allows adequate parametric control over processing parameters to assure adequate sterility levels can eliminate the need for an observation period following treatment and, thus, would be highly advantageous.
It is generally accepted that terminally sterilized articles, such as those used for medical or food applications, must attain greater than a 10xe2x88x926 survivor probability among microbial contaminants. In other words, there must be less than once chance in a million that viable microorganisms are present in or on the sterilized article. This level of sterilization is referred to as a sterility assurance level of 10xe2x88x926.
Another approach to sterilization of packages, for example, parenteral and enteral containers, involves presterilizing the containers using, for example, autoclaving, gamma radiation, chemical treatments or the like, and then filling such containers in an aseptic environment. A sterility assurance level of 10xe2x88x926 is frequently needed for such packages, particularly for containers for parenteral and enteral applications, and is difficult to verify using heretofore known aseptic filling approaches. (Current aseptic processes are validatable at sterility confidence levels of more than approximately 10xe2x88x923 by the use of media fills to demonstrate the absence of growth potential.) Thus, the U.S. Food and Drug Administration (USFDA), for example, has stated its preference for terminal sterilization processes, even though it recognizes that many products and product packages are damaged by such processes.
Therefore, what is needed is an approach to deactivating microorganisms at and/or within a target object, which approach achieves an easily verifiable sterility assurance level of at least, for example, 10xe2x88x926, but which approach also reduces damage to the target object, including, where present, packaging thereof, such as can occur with current terminal sterilization techniques, such as autoclaving or gamma radiation treatment.
The present invention advantageously addresses the above and other needs.
The present invention advantageously addresses the needs above as well as other needs by providing methods and apparatus for the deactivation of microorganisms, within and/or on the surface of a target object, using high-intensity, short-duration pulses of polychromatic light in a broad spectrum. More particularly, provided herein are methods and apparatus employing a photo-sensitive detector to monitor and adjust for the deactivation of microorganisms within and/or on the surface of a target object, thereby providing parametric control of the deactivation process such that deactivation of microorganisms is optimized and, most advantageously, providing validation of the sterilization.
Further provided herein is a method of optimizing deactivation of microorganisms on and/or within a target object, using high-intensity, short-duration pulses of polychromatic light in a broad spectrum, by automatically adjusting the intensity and/or duration of light exposure based upon parametric detection of the light. In particular, a photo-sensitive detector is employed to receive a portion of each pulse of light as a measure of the amount of light illuminating the target object and that measurement is used to calculate the degree of deactivation of microorganisms occurring at the surface and/or within the target object. In response to the measurements taken and calculations made, the intensity and/or duration of the pulsed light is adjusted to provide optimized deactivation. Further, these measurements can be, quite advantageously, used to validate sterilization of the target object(s).
In one embodiment, the present invention can be characterized as an apparatus for sterilizing microorganisms at a target object. Such apparatus employs a flashlamp system including means for generating high-intensity, short-duration pulses of polychromatic light in a broad spectrum, and for deactivating microorganisms at and/or within the target object by illuminating the target object with the pulses of light having been generated; a photo-sensitive detector positioned so as to receive a portion of each of the pulses of light as a measure of an amount of light illuminating the target object, for generating an output signal in response thereto; and a control system, coupled to the flashlamp system and the photo-sensitive detector, for determining, in response to the output signal, whether the pulses of light are sufficient to effect a prescribed level of deactivation of microorganisms in and/or on the target object.
In another embodiment, the present invention can be characterized as a method for sterilizing microorganisms on and/or in a target object, having steps of generating a high-intensity, short-duration pulse of polychromatic light in a broad spectrum; deactivating microorganisms at the target object by directing the pulse of light having been generated at the target object; receiving a portion of the pulse of light as a measure of an amount of the pulse of light illuminating the target object; generating an output signal in response to the receiving of the portion of the pulse of light; and determining, in response to the generating of the output signal, whether the pulse of light is sufficient to effect a prescribed level of deactivation of microorganisms in the target object, for example, such that the sterilization process is thereby validated, such as to sterility assurance level of at least about 10xe2x88x926.
In a further embodiment, the present invention provides an approach for deactivating microorganisms, and more particularly for deactivating microorganisms within parenteral and/or enteral solutions and packages or containers or contact lens solutions and packages and/or ophthalmic solutions and packages, and within product contents of such packages, using high-intensity, short-duration pulses of incoherent, polychromatic light in a broad spectrum directed at the packages, filled and/or empty, so as to penetrate the packages and deactivate microorganisms on an interior surface thereof and/or suspended within the volume or product contained within the packages.
In a still further embodiment, the invention can be characterized as an apparatus for sterilizing microorganisms in a container. Such apparatus employs the container, which may include, for example, a polyolefin, such as polyethylene, and which transmits light in a spectrum containing wavelengths selected from between about 120 nm and about 2600 nm, e.g., wavelengths between 180 nm and 1500 nm or, e.g., between 180 nm and 300 nm. The container is coupled to a port through which a product within the container can be withdrawn. The port may be, for example, a plastic tube or cap having a puncture site at which it is designed to be punctured for administration of its contents, or may be a cap that is unscrewed or otherwise removed before administration. Such ports are well known in the art. A flashlamp system generates high-intensity, short-duration pulses of polychromatic light in a broad spectrum, and the pulses of light generated by the flashlamp illuminate the container and deactivate microorganisms within the container.
In a variation of this further embodiment, an interface region at which the port is bonded to the container is also illuminated and microorganisms within the port and at the interface region are deactivated by the high-intensity, short-duration pulses of incoherent, polychromatic light in a broad spectrum.
In another embodiment, the invention may be characterized as an apparatus for deactivating microorganisms in a container that employs the container, which, in this embodiment, contains a transmissive product that transmits more than about one percent of light at a wavelength of about 260 nm, and which container transmits light in a spectrum having wavelengths selected from between 120 nm and 2600 nm (see examples above). The embodiment also employs a port coupled to the container through which the product within the container can be withdrawn, and a flashlamp system that generates high-intensity, short-duration pulses of polychromatic light in a broad spectrum, and deactivates microorganisms within the container by illuminating the container with such pulses of light.
In a further embodiment, the invention can be characterized as an apparatus for deactivating microorganisms in a container. The apparatus of this embodiment employs the container, which in this embodiment transmits light in a spectrum including wavelengths selected from between about 120 nm and about 2600 nm (see examples above); and a port coupled to the container through which a product within the container can be withdrawn; and a flashlamp system that generates high-intensity, short-duration pulses of polychromatic light in a broad spectrum, and deactivates microorganisms within the container and port by illuminating the container and port with the pulses of light.
In an additional embodiment, the invention can be characterized as an apparatus for deactivating microorganisms in a container employing the container, which includes at least one port through which the product within the container can be withdrawn, and transmits light in a spectrum having wavelengths selected from between about 120 nm and about 2600 nm (see examples above); a flashlamp system that generates high-intensity, short-duration pulses of polychromatic light in a broad spectrum, and deactivates microorganisms within the container by illuminating the container with the pulses of light having been generated. The flashlamp of this embodiment advantageously deactivates sufficient microorganisms to achieve a sterility assurance level of at least 10xe2x88x926.
In yet another embodiment, the invention can be characterized as an apparatus for sterilizing microorganisms in a container. The container of such embodiment includes a blister formed therein, and a backing material that together with the blister forms a cavity in which is contained a contact lens and a preservative fluid. The preservative fluid is at least one percent transmissive to light having a wavelength of about 260 nm. A flashlamp system generates high-intensity, short-duration pulses of polychromatic light in a broad spectrum that deactivate microorganisms within the container by illuminating the container with the pulses of light having been generated.